Platinum (IV) complex, production process thereof and carcinostatic agent containing the same

ABSTRACT

A platinum(IV) complex represented by the general formula (I): ##STR1## wherein R 1  and R 2  independently represent ammonia, an alkylamine or a cycloalkylamine, or R 1  and R 2  may together form a cycloalkyldiamine; X 1  and X 2  independently represent a halogen, nitrate ion, sulfate ion or a monocarboxylic acid, or X 1  and X 2  may together form a glycolate or a dicarboxylic acid; Y 1  represents formic acid, a C 1  -C 8  alkyl-, alkenyl-, aryl-, aralkyl-, alkylamino- or alkoxyl-monocarboxylic acid or sulfonic acid; and Y 2  represents a halogen. The complex of the invention is stable even when orally administered and has high antitumor activity.

This application is the national phase of PCT/JP96/00463 filed Feb. 26,1996.

TECHNICAL FIELD

This invention relates to a novel platinum(IV) complex which showsstrong antitumor activity, a process for the production thereof and acarcinostatic agent that contains the same.

BACKGROUND ART

Since the development and practical use of cisplatin as an effectiveantitumor agent, a broad range of studies have been conducted with theaim of finding a new platinum complex which possesses more effectiveantitumor activity than cisplatin, and of improving properties thereofother than the antitumor action, such as reduction of toxicity and otherundesirable side effects.

Carboplatin is known as a platinum(II) complex, as well as recentlydeveloped oxaliplatin. With regard to platinum(IV) complexes, iproplatinis known, and tetraplatin has been subjected to clinical trial but itsclinical development has been suspended due to the side effects, such astoxicity.

Each of these platinum complexes is for parenteral administration useand is hydrophilic. In order to improve quality of life of cancerpatients, great concern has been directed toward the development of anoral preparation for use in the treatment of cancer patients at theterminal stage.

DISCLOSURE OF THE INVENTION

The present invention provides platinum(IV) complexes having highantitumor activity, particularly for use in oral administration. Many ofthese complexes show high solubility in both water and organic solvents,have high partition coefficient and are stable in strongly acidicsolution.

The present invention is a platinum(IV) complex represented by thegeneral formula (I): ##STR2## wherein R₁ and R₂ independently representammonia, an alkylamine or a cycloalkylamine, or R₁ and R₂ may togetherform a cycloalkyldiamine; X₁ and X₂ independently represent a halogen,nitrate ion, sulfate ion or a monocarboxylic acid, or X₁ and X₂ maytogether form a glycolate or a dicarboxylic acid; Y₁ represents formicacid, a C₁ -C₈ alkyl-, alkenyl-, aryl-, aralkyl-, alkylamino- oralkoxyl-monocarboxylic acid or sulfonic acid; and Y₂ represents ahalogen.

In the general formula (I), the alkylamine includes normal and isoforms, and examples of the cycloalkyldiamine include cyclopentyldiamine,cyclohexyldiamine, cycloheptyldiamine and cyclooctyldiamine, each ofwhich may be a cis, trans-d or trans-l isomer of 1,2-, 1,3- or 1,4-form,1,1-diaminomethylcyclohexane, 1,1-diaminocyclopentane,1,1-diaminocycloheptane, 1,1-diaminocyclooctane, cis-d, cis-l, trans-dand trans-l isomers of 1-aminomethyl-2-aminomethylcyclohexane and cis-dland trans-dr isomers thereof, cis-d, cis-l, trans-d and trans-l isomersof 1-aminomethyl-2-aminomethylcyclopentane and cis-dl and trans-dlisomers thereof, cis-d, cis-l, trans-d and trans-l isomers of1-aminomethyl-2-aminomethylcycloheptane and cis-dl and trans-dl isomersthereof, cis-d, cis-l , trans-d and trans-e isomers of1-aminomethyl-2-aminomethylcyclooctane and cis-dl and trans-dl isomersthereof and the like.

In the general formula (I), examples of the monocarboxylic acid includegluconic acid, glucuronic acid and the like sugar carboxylic acids andan alkyl monocarboxylic acid, and examples of the dicarboxylic acidinclude oxalic acid, malonic acid and derivatives thereof (such as ofmethyl, ethyl, benzyl, benzoyl or the like) and1,1-cyclobutanedicarboxylic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a reaction scheme regarding the process for the productionof the platinum(IV) complex of the present invention.

FIG. 2 is a chart showing infrared absorption spectrum of C6-OHP.Cl as amember of the platinum(IV) complex of the present invention.

BEST MODE OF CARRYING OUT THE INVENTION

A preferred platinum complex of the present invention is a complexrepresented by the general formula (II): ##STR3## wherein Y₁ and Y₂ areas defined in the general formula (I).

A more preferred platinum complex of the present invention is a platinumcomplex represented by the general formula (II) wherein Y₁ is a C₂ -C₈alkyl monocarboxylic acid and Y₂ is a halogen.

A characteristic nature of the present invention is that amonocarboxylic acid or a sulfonic acid and a halogen element arecoordinated simultaneously at the trans position.

The following shows abbreviations to be used herein. cis, trans, cis:c-t-c

dach: 1,2-cyclohexanediamine (cis-dach, R,S-dach; trans-d-dach,

1S,2S-dach; trans-2-dach, 1R,2R-dach)

amcha: 2(aminomethyl)cyclohexylamine (cis-d, 1S,2S-amcha; cis-l,

1R,2R-amcha; trans-d, 1S,2R-amcha; trans-l, 1R,2S-amcha)

C5-OHP: t,c,c- [Pt (OCOC₄ H₉)₂ (ox) (1R,2R-dach)]

lQ-OHP: [Pt(ox) (1R,2R-dach)]

C5-OHP-Cl: t,t,c,c-[PtCl(OCOC₄ H₉)(ox)(1R,2R-dach)]

C5-OHP-Br: t,t,c,c-[PtBr(OCOC₄ H₉)(ox)(1R,2R-dach)]

C5-OHP-I: t,t,c,c-[PtI(OCOC₄ H₉)(ox)(1R,2R-dach)]

C4-OHP: t,c,c- [Pt (OCOC₃ H₇)₂ (ox) (1R,2R-dach)]

C4-OHP-Hal: t,t,c,c-[PtHal(OCOC₃ H₇)(ox)(1R,2R-dach)]

C6-OHP: t,c,c- [Pt (OCOC₅ H₁₁)₂ (ox) (1R,2R-dach)]

C6-OHP-Hal: t, t,c,c-[PtHal(OCOC₅ H₁₁) (ox) (1R,2R-dach)]

l-OHP Cl: t-[PtCl₂ (ox)(1R,2R-dach)]

l-OHP-Br: t-[PtBr₂ (Ox)(1R,2R-dach)]

l-OHP-I: t-[PtI₂ (ox)(1R,2R-dach)]

C4-COOAg: Ag-butylate

C5-COOAg: Ag-valerate

C6-COOAg: Ag-hexanoate

C7-COOAg: Ag-heptanoate

Hal: Cl, Br, I or F

ox: oxalate

mal: malonate

cbdca: 1,1-cyclobutane dicarboxylate

HPLC: high performance liquid chromatography

It was found that, when C4-OHP, C5-OHP, C6-ORP or the like Cn-OHP isorally administered, one carboxylic acid thereof is graduallysubstituted by Cl in the strongly acidic gastric juice (1 N HCl, pH0.1).

When C5-OHP is allowed to undergo 24 hours of reaction in a strong acidand then subjected to separation by HPLC, [PtCl(OCOC₄ H₉) (oxalato)(1R,2R-dach)], namely C5.OHP Cl, can be produced. In the same manner,[PtCl(OCOC₃ H₇) (oxalato) (lR,2R-dach)], namely C4-OHP.Cl, [PtCl (OCOC₅H₁₁) (oxalato) (1R,2R-dach)], namely C6-OHP.Cl, and [PtCl(OCOC₆ H₁₃)(oxalato) (1R,2R-dach)], namely C7-OHP.Cl, can be produced from C4-OHP,C6-OHP and C7-OHP, respectively.

The platinum complex of the present invention can also be synthesized bythe following alternative method. A methanol solution of l-OHP-Cl(or Bror I) as [PtCl₂ (or Br₂ or I₂)(oxalato)(1R,2R-dach)] is allowed toundergo 24 hours of reaction, while stirring in the dark at roomtemperature, with 1M of C5-COOAg (this can be obtained as whiteprecipitate by adding silver nitrate to n-valeric acid and then addingalcohol thereto; C4-COOAg, C6-COOAg, C7-COOAg and the like can also besynthesized in the same manner and used instead thereof). Afterfiltering off the thus formed AgCl, methanol is evaporated, the residueis dissolved in ethanol, activated carbon is added to the solution andfiltered off and then water is added to the filtrate to collect the thusformed precipitate by filtration. In the same manner, C4-OHP.Cl,C6-OHP.Cl and C7-OHP.Cl can be produced.

By using l-OHP.Cl, l-OHP.Br or l-OHP.I as the starting material andallowing it to react with C4-COOAg, C5-COOAg, C6-COOAg or C7-COOAg, alarge amount of C4-OHP.Cl(or Br or I), C5-OHP-Cl(or Br or I),C6-OHP.Cl(or Br or I) or C7-OHP.Cl(or Br or I) can be produced.According to this process, various types of complexes can be producedfrom C₁₋₈ COOAg.

The aforementioned two synthetic processes are shown in FIG. 1.

The platinum(IV) complexes of the present invention show antitumoractivity when orally administered for the treatment of malignant tumors.In consequence, these complexes can be made into dosage forms suitablefor oral administration, such as tablets, pills, capsules, liposomeinclusions and sterile suspensions, as well as suppositories, liniments,ointments, solutions and the like. Usual pharmaceutical carriers,additives, binders and/or fillers can also be used. They can be usedalso for parenteral administration as freeze-dried preparations andsolutions.

As fillers, diluents and auxiliaries of oral administrationpreparations, one or more materials can be used which may be selectedfrom lactose, sucrose, glucose, sorbitol, mannitol, potato starch,amylopectin, other various starches, cellulose derivatives (for example,carboxymethyl cellulose, hydroxyethyl cellulose and the like), gelatin,magnesium stearate, polyvinyl alcohol, calcium stearate, polyethyleneglycol, gum arabic, talc, titanium dioxide, vegetable oils such as oliveoil, peanut oil, sesame oil and the like, paraffin oils, neutral fatbases, ethanol, propylene glycol, physiological saline, sterile water,glycerol and the like.

As fillers for injection use, sugar solutions, buffer solutions,ethylene glycol, polyethylene glycol and the like can be used.

It is desirable to use the complex of the present invention in an amountof from 0.01 to 200 mg/kg, preferably from 0.1 to 100 mg/kg, morepreferably from 0.5 to 50 mg/kg, in the case of parenteraladministration, or from 0.1 to 2,000 mg/kg, preferably from 1 to 1,000mg/kg, more preferably from 5 to 500 mg/kg, in the case of oraladministration.

The platinum complex of the present invention does not show renaltoxicity, cross-resistance, mutagenicity and the like which becomemedicinal problems.

EXAMPLES

Examples of the present invention are given below by way of illustrationand not by way of limitation.

Example 1

Formation of C4-OHP.Cl

A 0.2 g portion of C4-OHP was dissolved in 20 ml of 1 N HCl and allowedto stand for 12 hours at 37° C. in the dark. After the reaction, theproduct was separated and purified by HPLC. Yield, 18 mg as colorlesspowder.

HPLC: Using Cosmosil 5C18 columns of 10 mm i.d. x 5 cm (guard column)and 15 mm i.d. x 25 cm (main column), 0.8 ml of the sample solution wasinjected and eluted at 50° C. with 30% MeOH at a rate of 3 ml/min.

Example 2

Formation of C5-OHP.Cl

A 0.4 g portion of C5-OHP was dissolved in 20 ml of 30% MeOH-1 N HClmixture solution and allowed to stand for 30 hours at 37° C. in thedark. After the reaction, the product was separated and purified byHPLC. Yield, 35 mg as colorless powder.

HPLC was carried out under the same conditions as described in Example1.

Example 3

Formation of C6-OHP.Cl

A 0.4 g portion of C6-OHP was dissolved in 17 ml of 50% MeOH-1 N HClmixture solution and allowed to stand for 36 hours at 37° C. in thedark. After the reaction, the product was separated and purified byHPLC. Yield, 35 mg as colorless powder.

HPLC was carried out under the same conditions as described in Example1.

Infrared absorption spectrum of the thus obtained C₆ -OHP.Cl is shown inFIG. 2, and results of the TLC analysis (development solvent:butanol/acetic acid/water=12:3:5) are shown below.

    ______________________________________                                        Complex            R.sub.f value                                              ______________________________________                                        l-OHP              0.13                                                         l-OHP · Cl (starting material) 0.24                                  C6-OHP · Cl 0.29                                                     C6-OHP 0.31                                                                 ______________________________________                                    

Example 4

Synthesis of C5-OHP.Br

A 1.12 g portion of [PtBr2(ox)(lR,2R-dach)], namely l-OHP.Br, wasdissolved in 140 ml of hot MeOH, and the solution was mixed with 0.42 gof 1M C5-COOAg and stirred for 48 hours at room temperature in the dark.After the reaction, the thus formed precipitate of AgBr was filteredoff, MeOH was evaporated to dryness, the resulting residue was dissolvedin 30 ml of EtOH, activated carbon was added to the solution andfiltered off and then the filtrate was concentrated and subjected toalumina or silica gel column chromatography to effect separation (fromthe starting material and C5-OHP) and purification. Yield, 0.85 g, 73%,as light yellow powder.

Example 5

Synthesis of C6-OHP.Br

A 1.12 g portion of l-OHP.Br was dissolved in 140 ml of MeOH, and thesolution was mixed with 0.44 g of 1M C6-COOAg and stirred for 48 hoursat room temperature in the dark. After the reaction, the thus formedAgBr was filtered off to carry out purification by the same treatment asdescribed in Example 4. Yield, 0.95 g, 80%, as light yellow powder.

Example 6

Synthesis of C5-OHP.I

A 0.65 g portion of l-OHP.I was dissolved in 100 ml of MeOH, and thesolution was mixed with 0.21 g of 1M C5-COOAg and stirred for 48 hoursat room temperature in the dark. Thereafter, the same treatment as inExample 4 was repeated. Yield, 0.45 g, 72%.

Example 7

Synthesis of C6-OHP.I

A 0.65 g portion of l-OHP.I was dissolved in 100 ml of MeOH, and thesolution was mixed with 0.22 g of 1M C6-COOAg and stirred for 48 hoursat room temperature in the dark. Thereafter, the same treatment as inExample 4 was repeated. Yield, 0.45 g, 71%.

Example 8

Synthesis of C5-OHP.Cl

A 0.47 g portion of l-OHP.Cl was dissolved in 40 ml of H₂ O+MeOH mixturesolution, and the solution was mixed with 0.21 g of 1M C5-COOAg andstirred for 48 hours at room temperature in the dark. Thereafter, thesame treatment as in Example 4 was repeated. Yield, 0.45 g, 85%.

Example 9

Synthesis of C6-OHP.Cl

A 0.47 g portion of l-OHP.Cl was dissolved in 40 ml of H₂ O+MeOH mixturesolution, and the solution was mixed with 0.19 g of 1M C6-COOAg andstirred for 48 hours at room temperature in the dark. Thereafter, thesame treatment as in Example 4 was repeated. Yield, 0.45 g, 85%.

Example 10

Synthesis of C4-OHP.Cl

Reaction of l-OHP.Cl and C4-COOAg was carried out in the same manner asdescribed in Examples 8 and 9. Yield, 0.45 g, 85%.

Analytical data of the thus obtained complexes are shown below.

1. Elemental analysis

    ______________________________________                                                C       H         N        Pt                                         ______________________________________                                        C4-OHP · Cl, C.sub.12 H.sub.27 N.sub.2 O.sub.6 PtCl                      calcd.    27.74;    4.04;   5.39                                            found 27.84; 4.75; 5.57                                                     C5-OHP · Cl, C.sub.13 H.sub.29 N.sub.2 O.sub.6 PtCl                      calcd.    29.26;    4.31;   5.25                                            found 29.16; 4.95; 5.10                                                     C6-OHP · Cl, C.sub.14 H.sub.31 N.sub.2 O.sub.6 PtCl                      calcd.    30.68;    4.56;   5.11;  35.61                                    found 29.69; 4.78; 5.03; 35.00                                              C5-OHP · Br, C.sub.13 H.sub.29 N.sub.2 O.sub.6 PtBr                      calcd.    26.98;    3.97;   4.87                                            found 26.94; 4.02; 4.87                                                     C6-OHP · Br, C.sub.14 H.sub.31 N.sub.2 O.sub.6 PtBr                      calcd.    28.37;    4.22;   4.72                                            found 27.36; 4.03; 4.59                                                     C5-OHP · I, C.sub.13 H.sub.29 N.sub.2 O.sub.6 PtI                        calcd.    24.96;    3.68;   4.48                                            found 24.85; 3.57; 4.40                                                     C6-OHP · I, C.sub.14 H.sub.31 N.sub.2 O.sub.6 PtI                        calcd.    26.29;    3.19;   4.38                                            found 26.30; 3.20; 4.40                                                     ______________________________________                                    

2. Partition coefficient

Partition coefficient (PC) of each of the thus obtained complexes to1-octanol/water is as follows.

    ______________________________________                                               Complex  PC                                                            ______________________________________                                               C4--OHP · Cl                                                                  3.6 × 10.sup.-2                                           C5--OHP · Cl 2.4 × 10.sup.-1                                   C6--OHP · Cl 8.4 × 10.sup.-1                                   C7--OHP · Cl 2.7                                                   ______________________________________                                    

3. Solubility

Solubility of each of the thus obtained complexes in water (about 20°C.) is shown below.

    ______________________________________                                        Complex        Solubility (mM)                                                ______________________________________                                        C4--OHP · Cl                                                                        147                                                              C5--OHP · Cl 41                                                      C6--OHP · Cl 9.6                                                     C7--OHP · Cl 2.2                                                   ______________________________________                                    

4. Stability

Stability of each of the thus obtained complexes in an aqueous solutionof hydrochloric acid at 37° C. is shown below in terms of its half life.

    ______________________________________                                                      Half life (hour)                                                Complex         0.05 M HCl                                                                              1 M HCl                                             ______________________________________                                        C4--OHP · Cl                                                                         >50       6.1                                                   C5--OHP · Cl >50 7.4                                                 C6--OHP · Cl N.D. 8.9                                                C7--OHP · Cl N.D. 11.3                                             ______________________________________                                    

The term N.D. indicates that significant decrease in concentration wasnot observed. The measurement was carried out at a complex concentrationof 50 μM at 37° C. in the dark.

5. Reduction property

Test results of the in vitro reduction of the thus obtained complexes byan ascorbic acid salt are shown below in terms of half life.

    ______________________________________                                                      Half life (hour)                                                Complex         5 mM    100 mM                                                ______________________________________                                        C4--OHP · Cl                                                                         0.6     <0.1                                                    C5--OHP · Cl 0.8 <0.1                                                C6--OHP · Cl 1.2 <0.1                                                C7--OHP · Cl 1.6 <0.1                                              ______________________________________                                    

The measurement was carried out at a complex concentration of 50 μM, pH7.5 (50 mM HEPES-NaOH buffer), at 37° C. in the dark.

Carcinostatic Test

ip: On the day 0, L 1210 (10⁵ cells/mouse) was transplanted into theabdominal cavity of each CDF₁ mouse, and each of the platinum complexeswas intraperitoneally administered on the day 1, day 5 and day 9(Q04D×03). Using 5 animals in one group, T/C % (T: treated, C: control)is calculated from survived days. A T/C % value of 125 or more wasjudged effective. The number of survived (or tumor bearing) animals isshown as n/5. A total of 10 mice were used in the control.

The results are shown below.

Carcinostatic effect ip--ip, L 1210, three administrations on days 1, 5and 9

    ______________________________________                                               100   50       25       12.5  mg/kg dose                               ______________________________________                                        C4--OHP · Cl                                                                  .sup.T 63                                                                             195      145    130   T/C%                                     C5--OHP · Cl .sup.T 88 283 (4/5) 168                                 C6--OHP · Cl .sup.T 80 280 (1/5) 173                                 C7--OHP · Cl  176 137 122                                            C5--OHP · Br  107 395 (4/5)                                          C6--OHP · Br .sup.T 69 .sup.T 96 373 (4/5)                         ______________________________________                                         T = toxic                                                                

L 1210 (10⁵ cells/mouse), one group=5 CDF₁ mice, ip administration onthe days 1, 5 and 9.

po: On the day 0, L 1210 (10⁵ cells/mouse) was transplanted into theabdominal cavity of each CDF₁ mouse, and each of the platinum complexeswas orally administered on the day 1, day 3, day 5, day 7 and day 9(Q02D×05), or on the day 1 to day 5 (Q01D×05). The oral administrationwas carried out with a 10, 7.5 or 5 times higher dose than the optimumamount of each platinum complex by ip (T/C % of ip; 100 mg/kg, 75 mg/kgor 50 mg/kg, respectively). A value of 140% or more was judgedeffective.

The results are shown below.

(Oral) carcinostatic effect L 1210, ip-po, every two days Q02D×05

    ______________________________________                                                   mg/kg dose                                                                    15   10         5      2.5                                         ______________________________________                                        C5--OHP · Cl                                                                      .sup.T 60                                                                            143        214  140                                         C6--OHP · Cl .sup.T 98 168 191 143                                   C7--OHP · Cl  151 129 117                                            C5--OHP · Br .sup.T 73 163 160                                       C6--OHP · Br .sup.T 88 180 173                                     ______________________________________                                         T = toxic                                                                

L 1210 (10⁵ cells/mouse); one group=5 CDF₁ mice; Suspension in olive oilwas administered into the stomach through a catheter.

I claim:
 1. A platinum(IV) complex represented by the general formula(I): ##STR4## wherein R₁ and R₂ independently represent ammonia, analkylamine or a cycloalkylamine, or R₁ and R₂ may together form a1,2-cycloalkyldiamine; X₁ and X₂ independently represent a halogen,nitrate ion, sulfate ion or a monocarboxylic acid, or X₁ and X₂ maytogether form a glycolate or a dicarboxylic acid; Y₁ represents formicacid, a C₁ -C₈ alkyl-monocarboxylic acid, alkenyl-monocarboxylic acid,aryl-monocarboxylic acid, aralkyl-monocarboxylic acid,alkylamino-monocarboxylic acid or alkoxyl-monocarboxylic acid orsulfonic acid; and Y₂ represents a halogen.
 2. The complex according toclaim 1 wherein it is represented by the general formula (II): ##STR5##wherein Y₁ and Y₂ are as defined in the general formula (I).
 3. Thecomplex according to claim 2 wherein Y₁ is a C₂ -C₈ alkyl monocarboxylicacid and Y₂ is a halogen.
 4. A carcinostatic agent which comprises aneffective amount of the platinum(IV) complex of claim 1 as an activeingredient.
 5. A process for producing a platinum(IV) complex ##STR6##wherein Y₁ is a C₂ -C₈ alkyl monocarboxylic acid and Y₂ is a halogenwhich comprises allowing a compound represented by the general formula(III): ##STR7## (wherein Y₂ represents a halogen) to react with a silversalt of a C₂ -C₈ alkyl monocarboxylic acid.
 6. A process for producing aplatinum(IV) complex ##STR8## Y₁ represents formic acid, a C₁ -C₈alkyl-monocarboxylic acid, alkenyl-monocarboxylic acid,aryl-monocarboxylic acid, aralkyl-monocarboxylic acid,alkylamino-monocarboxylic acid or alkoxyl-monocarboxylic acid orsulfonic acid; and Y₂ represents a halogen which comprises allowing acompound represented by the general formula (IV): ##STR9## (wherein Y₁is as defined for general formula to react with a hydrogen halide.
 7. Acarcinostatic agent comprising an effective amount of the platinum (IV)complex of claim
 2. 8. A carcinostatic agent comprising an effectiveamount of the platinum (IV) complex of claim 3.